Hydroxyamidine and hydroxyguanidine compounds as urokinase inhibitors

Abstract

The present invention relates to novel compounds for inhibiting the urokinase plasminogen activator (uPA), which have high bioavailability and oral administerability, and also to the use thereof as therapeutic active compounds for the treatment of urokinase- or/and urokinase receptor-associated disorders such as, for example, tumors and metastasizing. The invention relates in particular to compounds containing hydroxyamidine or hydroxyguanidine groups.

1 . A pharmaceutical composition, which comprises, as an active compound, at least one compound of the formula 
     
       
         
         
             
             
         
       
     
     wherein E is 
     
       
         
         
             
             
         
       
       B is —SO 2 — or —CO—; 
       X is —NR 1  or —CHR 1 ; 
       Z is —R 4 , —OR 4  or —NH—R 4 ; 
       Y is —OR 2  or —NHR 2 ; 
       R 1  is in each case independently —H, —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl or —C 2 -C 6 -alkynyl, unsubstituted or substituted; 
       R 2  is —H, —OR 1 , —COR 1 , —CON(R 1 ) 2  or —COOR 1 ; 
       R 3  is —H, —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl or —C 2 -C 6 -alkynyl, unsubstituted or substituted, or —COR 6  or —COOR 6  or an oligo- or polyalkyleneoxy radical; 
       R 4  is —H, —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl or —C 2 -C 6 -alkynyl, unsubstituted or substituted, or a cyclic radical; 
       R 6  is —H, —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl or —C 2 -C 6 -alkynyl, or a radical selected from the group consisting of a cycloalkyl-, aryl-, and bicyclic-radical which is unsubstituted or substituted by at least one substituent selected from the group consisting of —C 1 -C 3 -alkyl, —C 1 -C 3 -alkoxy, halogen, —OR 6 , ═O, —NO 2 , —CN, —COOR 6 , —N(R 6 ) 2 , —NR 6 COR 6 , —NR 6 CON(R 6 ) 2  and —OCOR 6 ; 
     
     said alkyl, alkenyl and alkynyl moieties being straight-chained or branched and being unsubstituted or substituted by at least one substituent selected from the group consisting of halogen, —OR 6 , —OCOR 6 , —N(R 6 ) 2 , —NR 6 COR 6 , —NR 6 CON(R 6 ) 2 , COOR 6 , and a radical selected from the group consisting of a cycloalkyl-, aryl-, and bicyclic-radical which is unsubstituted or substituted by at least one substituent selected from the group consisting of —C 1 -C 3 -alkyl, —C 1 -C 3 -alkoxy, halogen, —OR 6 , ═O, —NO 2 , —CN, —COOR 6 , —N(R 6 ) 2 , —NR 6 COR 6 , —NR 6 CON(R 6 ) 2  and —OCOR 6 , or a salt of said compound; 
     and a pharmaceutically customary carrier, diluent or/and adjuvant. 
   
   
       2 . The pharmaceutical composition of  claim 1 , wherein said composition further comprises a compound of the formula 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 3 , R 4 , and R 6  are as defined in  claim 1 ; or a salt of said compound. 
   
   
       3 . The pharmaceutical composition of  claim 1 , wherein R 4  is 
     
       
         
         
             
             
         
       
     
   
   
       4 . The pharmaceutical composition of  claim 1 , wherein R 4  is a substituted or unsubstituted C 1 -C 3 -alkyl-aryl radical, wherein said substituted C 1 -C 3 -alkyl-aryl radical is substituted in at least on of the meta- and para-positions with a substituent selected from the group consisting of halogen and αα-NO 2 . 
   
   
       5 . The pharmaceutical composition of  claim 1 , wherein said active compound is selected from the group consisting of
 benzylsulfonyl-(D)-Ser-Gly-(4-hydroxyguanidinobenzyl)amide;   4-chlorobenzylsulfonyl-(D)-Ser-N-Me-Ala-(4-hydroxyguanidinobenzyl)amide;   4-chlorobenzylsulfonyl-(D)-Ser-Gly-(4-hydroxyguanidinobenzyl)amide;   benzylsulfonyl-(D)-Ser-N-Me-Gly-(4-hydroxyguanidinobenzyl)amide; and   4-chlorobenzylsulfonyl-(D)-Ser-Ala-(4-hydroxyguanidinobenzyl)amide;   or a physiologically compatible salt thereof.   
   
   
       6 . The pharmaceutical composition of  claim 5 , in which the compound is benzylsulfonyl-(D)-Ser-Gly-(4-hydroxyguanidinobenzyl)amide hydrogen sulfate or benzylsulfonyl-(D)-Ser-Gly-(4-hydroxyguanidinobenzyl)amide sulfate. 
   
   
       7 . The pharmaceutical composition of  claim 1 , wherein said composition is in an orally administrable form. 
   
   
       8 . The pharmaceutical composition of  claim 1 , wherein said compound is present as a sulfate or hydrogen sulfate salt. 
   
   
       9 . A method for treating a tumor susceptible to urokinase inhibition associated with pathological overexpression of urokinase and/or urokinase receptor comprising administering to a subject in need of such treatment a pharmaceutically effective amount of at least one compound of the formula 
     
       
         
         
             
             
         
       
     
     wherein E is 
     
       
         
         
             
             
         
       
       B is —SO 2 — or —CO—; 
       X is —NR 1  or —CHR 1 ; 
       Z is —R 4 , —OR 4  or —NH—R 4 ; 
       Y is —OR 2  or —NHR 2 ; 
       R 1  is in each case independently —H, —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl or —C 2 -C 6 -alkynyl, unsubstituted or substituted; 
       R 2  is —H, —OR 1 , —COR 1 , —CON(R 1 ) 2  or —COOR 1 ; 
       R 3  is —H, —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl or —C 2 -C 6 -alkynyl, unsubstituted or substituted, or —COR 6  or —COOR 6  or an oligo- or polyalkyleneoxy radical; 
       R 4  is —H, —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl or —C 2 -C 6 -alkynyl, unsubstituted or substituted, or a cyclic radical; 
       R 6  is —H, —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl or —C 2 -C 6 -alkynyl, or a radical selected from the group consisting of a cycloalkyl-, aryl-, and bicyclic-radical which is unsubstituted or substituted by at least one substituent selected from the group consisting of —C 1 -C 3 -alkyl, —C 1 -C 3 -alkoxy, halogen, —OR 6 , ═O, —NO 2 , —CN, —COOR 6 , —N(R 6 ) 2 , —NR 6 COR 6 , —NR 6 CON(R 6 ) 2  and —OCOR 6 ; 
     
     said alkyl, alkenyl and alkynyl moieties being straight-chained or branched and being unsubstituted or substituted by at least one substituent selected from the group consisting of halogen, —OR 6 , —OCOR 6 , —N(R 6 ) 2 , —NR 6 COR 6 , —NR 6 CON(R 6 ) 2 , COOR 6  , and a radical selected from the group consisting of a cycloalkyl-, aryl-, and bicyclic-radical which is unsubstituted or substituted by at least one substituent selected from the group consisting of —C 1 -C 3 -alkyl, —C 1 -C 3 -alkoxy, halogen, —OR 6 , ═O, —NO 2 , —CN, —COOR 6 , —N(R 6 ) 2 , —NR 6 COR 6 , —NR 6 CON(R 6 ) 2  and —OCOR 6 , or a salt of said compound. 
   
   
       10 . The method of  claim 9 , wherein the tumor is a primary tumor susceptible to urokinase inhibition. 
   
   
       11 . The method of  claim 9 , wherein the compound is in a composition which is in a form suitable for oral administration. 
   
   
       12 . The method of  claim 9 , wherein the compound is in a composition which is in the form of tablets, coated tablets, capsules, pellets, a solution, an emulsion or/and suspension. 
   
   
       13 . The method of  claim 9 , wherein the living organism is a human. 
   
   
       14 . The method of  claim 9 , wherein said disease is lung cancer, breast cancer, colon carcinoma, pancreatic carcinoma, or metastases thereof. 
   
   
       15 . A method for treating diseases characterized by the formation of metastases associated with pathological overexpression of urokinase and/or urokinase receptor comprising administering to a subject in need of such treatment a pharmaceutically effective amount of at least one compound of the formula 
     
       
         
         
             
             
         
       
     
     wherein E is 
     
       
         
         
             
             
         
       
       B is —SO 2 — or —CO—; 
       X is —NR 1  or —CHR 1 ; 
       Z is —R 4 , —OR 4  or —NH—R 4 ; 
       Y is —OR 2  or —NHR 2 ; 
       R 1  is in each case independently —H, —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl or —C 2 -C 6 -alkynyl, unsubstituted or substituted; 
       R 2  is —H, —OR 1 , —COR 1 , —CON(R 1 ) 2  or —COOR 1 ; 
       R 3  is —H, —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl or —C 2 -C 6 -alkynyl, unsubstituted or substituted, or —COR 6  or —COOR 6  or an oligo- or polyalkyleneoxy radical; 
       R 4  is —H, —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl or —C 2 -C 6 -alkynyl, unsubstituted or substituted, or a cyclic radical; 
       R 6  is —H, —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl or —C 2 -C 6 -alkynyl, or a radical selected from the group consisting of a cycloalkyl-, aryl-, and bicyclic-radical which is unsubstituted or substituted by at least one substituent selected from the group consisting of —C 1 -C 3 -alkyl, —C 1 -C 3 -alkoxy, halogen, —OR 6 , ═O, —NO 2 , —CN, —COOR 6 , —N(R 6 ) 2 , —NR 6 COR 6 , —NR 6 CON(R 6 ) 2  and —OCOR 6 , 
     
     said alkyl, alkenyl and alkynyl moieties being straight-chained or branched and being unsubstituted or substituted by at least one substituent selected from the group consisting of halogen, —OR 6 , —OCOR 6 , —N(R 6 ) 2 , —NR 6 COR 6 , —NR 6 CON(R 6 ) 2 , COOR 6  , and a radical selected from the group consisting of a cycloalkyl-, aryl-, and bicyclic-radical which is unsubstituted or substituted by at least one substituent selected from the group consisting of —C 1 -C 3 -alkyl, —C 1 -C 3 -alkoxy, halogen, —OR 6 , ═O, —NO 2 , —CN, —COOR 6 , —N(R 6 ) 2 , —NR 6 COR 6 , —NR 6 CON(R 6 ) 2  and —OCOR 6 , or a salt of said compound. 
   
   
       16 . A compound of the formula 
     
       
         
         
             
             
         
       
     
     wherein E is 
     
       
         
         
             
             
         
       
       B is —SO 2 — or —CO—; 
       X is —NR 1  or —CHR 1 , 
       Z is —R 4 , —OR 4  or —NH—R 4 ; 
       Y is —OR 2  or —NHR 2 ; 
       R 1  is in each case independently —H, —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl or —C 2 -C 6 -alkynyl, unsubstituted or substituted; 
       R 2  is —H, —OR 1 , —COR 1 , —CON(R 1 ) 2  or —COOR 1 ; 
       R 3  is —H, —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl or —C 2 -C 6 -alkynyl, unsubstituted or substituted, or —COR 6  or —COOR 6  or an oligo- or polyalkyleneoxy radical; 
       R 4  is —H, —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl or —C 2 -C 6 -alkynyl, unsubstituted or substituted, or a cyclic radical; 
       R 6  is —H, —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl or —C 2 -C 6 -alkynyl, or a radical selected from the group consisting of a cycloalkyl-, aryl-, and bicyclic-radical which is unsubstituted or substituted by at least one substituent selected from the group consisting of —C 1 -C 3 -alkyl, —C 1 -C 3 -alkoxy, halogen, —OR 6 , ═O, —NO 2 , —CN, —COOR 6 , —N(R 6 ) 2 , —NR 6 COR 6 , —NR 6 CON(R 6 ) 2  and —OCOR 6 ; 
     
     said alkyl, alkenyl and alkynyl moieties being straight-chained or branched and being unsubstituted or substituted by at least one substituent selected from the group consisting of halogen, —OR 6 , —OCOR 6 , —N(R 6 ) 2 , —NR 6 COR 6 , —NR 6 CON(R 6 ) 2 , COOR 6 , and a radical selected from the group consisting of a cycloalkyl-, aryl-, and bicyclic-radical which is unsubstituted or substituted by at least one substituent selected from the group consisting of —C 1 -C 3 -alkyl, —C 1 -C 3 -alkoxy, halogen, —OR 6 , ═O, —NO 2 , —CN, —COOR 6 , —N(R 6 ) 2 , —NR 6 COR 6 , —NR 6 CON(R 6 ) 2  and —OCOR 6 , or a salt of said compound. 
   
   
       17 . The compound of  claim 16 , wherein R 4  is 
     
       
         
         
             
             
         
       
     
   
   
       18 . The compound of  claim 16 , wherein R 4  is a substituted or unsubstituted C 1 -C 3 -alkyl-aryl radical, wherein said substituted C 1 -C 3 -alkyl-aryl radical is substituted at least on one of the meta- and para-positions with a substituent selected from the group consisting of halogen and αα-NO 2 . 
   
   
       19 . A compound selected from the group consisting of
 benzylsulfonyl-(D)-Ser-Gly-(4-hydroxyguanidinobenzyl)amide;   4-chlorobenzylsulfonyl-(D)-Ser-N-Me-Ala-(4-hydroxyguanidinobenzyl)amide;   4-chlorobenzylsulfonyl-(D)-Ser-Gly-(4-hydroxyguanidinobenzyl)amide,   benzylsulfonyl-(D)-Ser-N-Me-Gly-(4-hydroxyguanidinobenzyl)amide; and   4-chlorobenzylsulfonyl-(D)-Ser-Ala-(4-hydroxyguanidinobenzyl)amide;   or a physiologically compatible salt thereof.   
   
   
       20 . The compound of  claim 19 , wherein said compound is benzylsulfonyl-(D)-Ser-Gly-(4-hydroxyguanidinobenzyl)amide hydrogen sulfate or benzylsulfonyl-(D)-Ser-Gly-(4-hydroxyguanidinobenzyl)amide sulfate. 
   
   
       21 . The compound of  claim 16 , wherein said compound is present as a sulfate or hydrogen sulfate salt.